Method for inhibiting acyl-CoA : cholesterol acyltransferase

ABSTRACT

Heterocyclic derivatives of the formula (I) ##STR1## wherein each symbol is as defined in the specification, pharmaceutically acceptable salts thereof and method of producing them. Pharmaceutical compositions containing the heterocyclic derivative or a pharmaceutically acceptable salt thereof, particularly, ACAT inhibitors and lipoperoxidation inhibitors. The heterocyclic derivatives and pharmaceutically acceptable salts thereof of the present invention show superior ACAT inhibitory activity and lipoperoxidation inhibitory activity, and are useful as ACAT inhibitors and hyperlipemia inhibitors. 
     To be specific, they are useful for the prevention and treatment of arteriosclerotic lesions of arteriosclerosis, hyperlipemia and diabetes, as well as ischemic diseases of brain, heart and the like.

This application is a divisional of 08/809,242, filed Mar. 19, 1997, nowU.S. Pat. No. 5,990,150, which is a 371 of PCT/JP95/01873, filed Sep.20, 1995.

TECHINICAL FIELD

The present invention relates to novel heterocyclic derivatives, amethod of production thereof and pharmaceutical use thereof. Moreparticularly, the present invention relates to novel heterocyclicderivatives having an indoline ring or tetrahydroquinoline ring, amethod of production thereof and pharmaceutical use thereof,specifically acyl--CoA: cholesterol acyltransferase (hereinafter ACAT)inhibitors and lipoperoxidation inhibitors.

BACKGROUND ART

It is a well-known fact that arteriosclerosis is an extremely importantfactor causing various circulatory diseases, and active studies havebeen undertaken in an attempt to achieve suppression of the evolution ofarterial sclerosis or regression thereof. In particular, although theusefulness of a pharmaceutical agent which reduces cholesterol in bloodor arterial walls has been acknowledged, an ideal pharmaceutical agentexhibiting positive clinical effects while causing less side-effects hasnot been realized.

In recent years, it has been clarified that cholesterol accumulated inarterial walls in the ester form thereof significantly evolvesarteriosclerosis. A decrease in cholesterol level in blood leads to thereduction of accumulation of cholesterol ester in arterial walls, and iseffective for the suppression of evolution of arteriosclerosis andregression thereof.

Cholesterol in food is esterified in mucous membrane of small intestine,and taken into blood as chylomicron. ACAT is known to play an importantrole in the generation of cholesterol ester in mucous membrane of smallintestine. Thus, if esterification of cholesterol can be suppressed byinhibiting ACAT in mucous membrane of small intestine, absorption ofcholesterol by mucous membrane and into blood can be presumablyprevented to ultimately result in lower cholesterol level in blood.

In arterial walls, ACAT esterifies cholesterol and causes accumulationof cholesterol ester. Inhibition of ACAT in arterial walls is expectedto effectively suppress accumulation of cholesterol ester.

From the foregoing, it is concluded that an ACAT inhibitor will make aneffective pharmaceutical agent for hyperlipemia and arteriosclerosis, asa result of suppression of absorption of cholesterol in small intestineand accumulation of cholesterol in arterial walls.

Conventionally, for example, there have been reported, as such ACATinhibitors, amide and urea derivatives [J. Med. Chem., 29 :1131 (1986),Japanese Patent Unexamined Publication Nos. 117651/1990, 7259/1990,32666/1993 and 327564/1992].

However, creation and pharmacological studies of these compounds havebeen far from sufficient.

Meanwhile, peroxidation of low density lipoprotein (LDL) is also highlyresponsible for accumulation of cholesterol ester in arterial walls. Inaddition, it is known that peroxidation of lipids in a living body isdeeply concerned with the onset of arteriosclerosis and cerebrovascularand cardiovascular ischemic diseases.

Accordingly, a compound having both ACAT inhibitory activity andlipoperoxidation inhibitory activity is highly useful as apharmaceutical product, since it effectively reduces accumulation ofcholesterol ester in arterial walls and inhibits lipoperoxidation in theliving body, thereby preventing and treating various vascular diseasescaused thereby.

It is therefore an object of the present invention to provide a compoundhaving ACAT inhibitory activity and lipoperoxidation inhibitoryactivity, a method for production thereof and pharmaceutical usethereof, particularly as an ACAT inhibitor and lipoperoxidationinhibitor.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies with the aim ofaccomplishing the above-mentioned object and found that a certainheterocyclic derivative having an indoline ring or tetrahydroquinolinering has lipoperoxidation inhibitory activity in addition to strong ACATinhibitory activity, and that said compound has strong anti-hyperlipemia effect and anti-arteriosclerosis effect, which resulted inthe completion of the invention.

Thus, the present invention relates to a heterocyclic derivative of theformula (I) ##STR2## wherein one of R¹, R², R³ and R⁴ is a group of theformula --NHCO--R⁶ wherein R⁶ is optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heterocycle, optionally substitutedheterocyclic alkyl, --R^(A) SO₃ A, --R^(B) PO₃ B where R^(A) and R^(B)are each alkylene and A and B are each alkali metal or hydrogen atom,--NR⁷ R⁸ where R⁷ is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl or optionally substituted arylalkyl and R⁸is hydrogen atom or lower alkyl, or --R⁹ --OCOR¹⁰ where R⁹ is alkyleneand R¹⁰ is optionally substituted alkyl, optionally substitutedheterocycle or optionally substituted heterocyclic alkyl, and theremaining three may be the same or different and each is independently ahydrogen atom, a lower alkyl or a lower alkoxy; R⁵ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkylalkyl, an optionally substituted aryl, anoptionally substituted arylalkyl, an optionally substituted heterocycle,an optionally substituted heterocyclic alkyl, an alkenyl, an alkynyl, adialkylaminoacyloxyalkyl, --R^(D) SO₃ D or --R^(E) PO₃ E where R^(D) andR^(E) are each alkylene and D and E are each alkali metal or hydrogenatom, provided that when R⁴ is --NHCO--R⁶, R⁵ and R⁶ optionallycombinedly form a ring; and m is 1 or 2,

[hereinafter this compound is also referred to as Compound (I)] and apharmaceutically acceptable salt thereof.

The present invention also relates to a method for producing theabove-mentioned heterocyclic derivative or a pharmaceutically acceptablesalt thereof, which comprises a step of

1 reacting an amine of the formula (II) ##STR3## wherein R¹¹, R¹² andR¹³ may be the same or different and each is independently hydrogenatom, lower alkyl or lower alkoxy, and R⁵ and m are as defined above[hereinafter also referred to as Compound (II)], and an isocyanate ofthe formula (III)

R⁷ NCO (III)

wherein R⁷ is as defined above [hereinafter also referred to as Compound(III)];

2 reacting Compound (II) and a halogen compound of the formula (IV)

R⁶ -COX (IV)

wherein X is halogen atom-and R⁶ is as defined above [hereinafter alsoreferred to as Compound (IV)];

3 reacting Compound (II) and a carboxylic acid of the formula (V)

R⁶ ' COOH (V)

wherein R⁶ ' is optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heterocycle or optionally substituted heterocyclic alkyl[hereinafter also referred to as Compound (V)] or a reactive derivativethereof;

4 reacting an isocyanate of the formula (VI) ##STR4## wherein R⁵, R¹¹,R¹², R¹³ and m are as defined above [hereinafter also referred to asCompound (VI)], and an amine of the formula (VII)

HNR⁷ R⁸ (VII)

wherein R⁷ and R⁸ are as defined above [hereinafter also referred to asCompound (VII)]; or

5 reacting a compound of the formula (VIII) ##STR5## wherein R¹, R², R³,R⁴ and m are as defined above [hereinafter also referred to as Compound(VIII)], and a compound of the formula (IX)

R⁵ X (ix)

wherein R⁵ and X are as defined above [hereinafter also referred to asCompound (IX)].

The present invention also relates to pharmaceutical compositions, ACATinhibitors and lipoperoxidation inhibitors containing theabove-mentioned heterocyclic derivative or a pharmaceutically acceptablesalt thereof.

In the present specification, each symbol denotes the following.

Lower alkyl at R¹ , R², R³, R⁴, R⁸, R¹¹, R¹² and R¹³ may be linear orbranched and preferably has 1 to 4 carbon atoms. Examples thereofinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl and the like.

Lower alkoxy at R¹, R², R³, R⁴, R¹¹, R¹² and R¹³ may be linear orbranched and preferably has 1 to 4 carbon atoms. Examples thereofinclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy and the like.

Alkyl at R⁵, R⁶, R⁶ ', R⁷ and R¹⁰ may be linear or branched andpreferably has 1 to 12 carbon atoms. Examples thereof include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl,1,1-dimethylpentyl, 1,1-dimethylhexyl, 3,3-dimethylbutyl,4,4-dimethylbutyl and the like.

Cycloalkyl at R⁵, R⁶, R⁶ ' and R⁷ preferably has 3 to 6 carbon atoms.Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

With regard to cycloalkylalkyl at R⁵, R⁶, R⁶ ' and R⁷, its cycloalkylmoiety preferably has 3 to 6 carbon atoms and alkyl moiety preferablyhas 1 to 3 carbon atoms. Examples of cycloalkylalkyl includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl and the like.

Examples of aryl at R⁵, R⁶, R⁶ ' and R⁷ include phenyl, naphthyl and thelike.

Arylalkyl at R⁵, R⁶, R⁶ ' and R⁷ has an aryl moiety as exemplified aboveand its alkyl moiety preferably has 1 to 4 carbon atoms. Examples ofarylalkyl include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl and the like.

Heterocycle group at R⁵, R⁶, R⁶ ' and R¹⁰ is a monovalent group whichoccurs as a result of liberation of one hydrogen atom bonded to the ringof heterocyclic compound and may be aliphatic or aromatic. Examplesthereof include pyrrolidinyl, piperidyl, piperidino, morpholinyl,morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl and the like.

Heterocyclic alkyl at R⁵, R⁶, R⁶ ' and R¹⁰ has a heterocyclic moiety asexemplified above and its alkyl moiety preferably has 1 to 8 carbonatoms. Examples thereof include (1-pyrrolidinyl)butyl, morpholinopropyl,1,1-dimethyl-2-(1-pyrrolidinyl)ethyl, 1,1-dimethyl-2-piperidinoethyl,1,1-dimethyl-3-(imidazol-1-yl)propyl, (2,6-dimethylpiperidino)methyl,(2,6-dimethylpiperidino)ethyl, (2,6-dimethylpiperidino)propyl and thelike.

The above-mentioned alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycle and heterocyclic alkyl may be substituted. Examples of thesubstituent include alkyl, amino, hydroxy, dialkylamino, aminoalkyl,alkoxy, carboxyl, alkoxycarbonyl, carboxyalkyl, acyloxy, phenyl,phenoxy, halogen atom and the like.

Alkyl in alkyl, dialkylamino, aminoalkyl and carboxyalkyl is exemplifiedby the above-mentioned lower alkyl. Alkoxy in alkoxy and alkoxycarbonylis exemplified by the above-mentioned lower alkoxy. Acyloxy may belinear or branched and preferably has 2 to 5 carbon atoms. Examplesthereof include acetyloxy, propionyloxy, butyryloxy, valeryloxy,pivaloyloxy and the like. Halogen atom is exemplified by those to bementioned later. Alkyl in dialkylamino may be substituted by phenyl.

Alkenyl at R⁵ may be linear or branched and preferably has 2 to 8 carbonatoms. Examples thereof include ethenyl, propenyl, isopropenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, 3,3-dimethyl-2-propenyl and thelike.

Alkynyl at R⁵ may be linear or branched and preferably has 2 to 8 carbonatoms. Examples thereof include ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl, octynyl, 3,3-dimethyl-2-propynyl and the like.

Alkyl moiety of dialkylaminoacyloxyalkyl at R⁵ preferably has 1 to 8carbon atoms, and its acyl moiety may be linear or branched andpreferably has 2 to 5 carbon atoms. Examples thereof include acetyl,propionyl, butyryl, valeryl, pivaloyl and the like. Thedialkylaminoacyloxyalkyl is specifically exemplified byN,N-dimethylaminoacetoxyethyl, N,N-dimethylaminoacetoxypropyl and thelike.

Alkylene at R^(A), R^(B), R^(D), R^(E) and R⁹ may be linear or branchedand preferably has 1 to 8 carbon atoms. Examples thereof includemethylene, ethylene, trimethylene, propylene, tetramethylene,pentamethylene, hexamethylene, 1,1-dimethylethylene,2,2-dimethylpropylene and the like.

Alkali metal at A, B, D and E is preferably sodium, potassium and thelike.

Halogen atom at X is exemplified by chlorine atom, bromine atom, iodineatom and the like.

When R⁴ is --NHCO--R⁶, R⁶ and R⁵ may combinedly form a ring. The group(--R⁶ --R⁵ --) formed by R⁶ and R⁵ in combination may be linear orbranched and preferably has 2 to 12 carbon atoms. Examples thereofinclude alkylene such as 1,1-dimethyltrimethylene,1,1-dimethyltetra-methylene, 2,2-dimethyltetramethylene,1,1-dimethylpentamethylene, 2,2-dimethylpentamethylene and the like, andalkylene having --OCO-- bond, such as --C(CH₃)₂ CH₂ OCO(CH₂)₃ --,--C(CH₃)₂ CH₂ OCOC(CH₃)₂ (CH₂)₃ -- and the like.

The preferable Compound (I) of the present invention includes, forexample,

1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea,

1-butyl-3-(1-hexyl-4,6-dimethylindolin-7-yl)urea,

N-(1-hexyl-4,6-dimethylindolin-5-yl)-2,2-dimethylpropanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,

N-(1-pentyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,

N-(1-isobutyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylbutanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpentanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-cyclohexanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-ethoxypropanamide,

N-(1-ethoxypropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-3-piperidinopro-panamide,

N-(1-piperidinopropyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide,

N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,6-dimethylpiperidinopropanamide,and the like, and pharmaceutically acceptable salts thereof.

The Compound (I) may be converted to a pharmaceutically acceptable saltthereof.

The Compound (I) may be converted to an acid addition salt, since it hasa basic group, and the acid to form this acid addition salt includes,for example, an inorganic acid such as hydrochloric acid, sulfuric acid,phosphoric acid, nitric acid and the like; an organic acid such asoxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid,methanesulfonic acid, toluenesulfonic acid and the like; and the like.

When Compound (I) has an acidic group such as carboxyl, it can form analkali metal salt such as sodium salt, potassium salt and the like;

alkaline earth metal salt such as calcium salt, magnesium salt and thelike; organic base salt such as triethylamine salt, dicyclohexylaminesalt, pyridine salt and the like; and the like.

The Compound (I) and pharmaceutically acceptable salts thereof can beproduced, for example, by the following methods.

Production Method 1

Compound (II) and compound (III) are reacted.

This method produces a compound of the formula (I) wherein R⁶ is --NR⁷R⁸ where R⁸ is hydrogen atom.

This reaction generally proceeds in an inert solvent. Examples of theinert solvent include acetone, dioxane, acetonitrile, chloroform,benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate, N,N-dimethylformamide, pyridine, water and the like, andmixtures thereof.

In addition, a base such as triethylamine, pyridine,4-dimethylaminopyridine, potassium carbonate and the like may be added.

The reaction temperature is generally from -10° C. to 160° C.,preferably 20-100° C., and the reaction time is generally from 30minutes to 10 hours.

The starting compound (II) can be prepared, for example, by thefollowing method.

A nitro group is introduced into a compound of the general formula##STR6## wherein R¹¹, R¹², R¹³ and m are as defined above and R¹⁴ is anamino-protecting group [see J. Eric. Mordlander, et al., J. Org. Chem.,46, 778-782 (1981)], (introduction of nitro onto benzene ring) usingnitric acid in a mixed solvent of acetic acid and sulfuric acid, and theamino-protecting group is eliminated. The compound thus obtained andcompound (IX) are reacted, and nitro group is reduced using a catalystsuch as palladium-carbon and the like to give starting compound (II).

Examples of the amino-protecting group at R¹⁴ include acyl such asformyl, acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl, propionyl, benzoyl and the like.

Said amino-protecting group is eliminated by a method known per se. Forexample, it is eliminated by the action of an acid (e.g., hydrochloricacid, formic acid, trifluoroacetic acid and the like) or an alkali(e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, sodiumhydrogencarbonate and the like), or other method.

Production Method 2

Compound (II) and compound (IV) are reacted.

This method produces a compound of the formula (I) wherein R⁶ can be anyone of those defined above.

This reaction generally proceeds in an inert solvent. Examples of theinert solvent include acetone, dioxane, acetonitrile, chloroform,benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate, N,N-dimethylformamide, pyridine, water and the like, andmixtures thereof.

In addition, a base such as triethylamine, pyridine,4-dimethylaminopyridine, potassium carbonate and the like may be added.

The reaction temperature is generally from -10° C. to 100° C.,preferably 0-60° C., and the reaction time is generally from 30 minutesto 10 hours.

Production Method 3

Compound (II) and compound (V) or a reactive derivative thereof arereacted.

This method produces a compound of the formula (I) wherein R⁶ is R⁶ '.

This reaction generally proceeds in an inert solvent. Examples of theinert solvent include acetone, dioxane, acetonitrile, chloroform,benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate, N,N-dimethylformamide, pyridine, water and the like, andmixtures thereof.

In addition, a base such as triethylamine, pyridine,4-dimethylaminopyridine, potassium carbonate and the like may be added.

The reaction temperature is generally from -10° C. to 100° C.,preferably 0-60° C., and the reaction time is generally from 30 minutesto 10 hours.

Compound (V) is subjected to said reaction as, for example, a free acid;a salt such as sodium, potassium, calcium, triethylamine, pyridine andthe like; or a reactive derivative such as acid anhydride, mixed acidanhydride [e.g., substituted phosphoric acid (e.g., dialkylphosphoricacid), alkyl carbonate (e.g., monoethyl carbonate) and the like], activeamide (e.g., amide with imidazole etc.), ester (e.g., cyanomethyl ester,4-nitrophenyl ester and the like), and the like.

When Compound (V) is used as a free acid or salt in this reaction, thereaction is preferably carried out in the presence of a condensingagent. Examples of the condensing agent include dehydrating agent suchas N,N'-di-substituted-carbodiimides (e.g.,N,N'-dicyclohexylcarbodiimide), carbodiimide compounds (e.g.,1-ethyl-3-(3'-dimethylamino-propyl)carbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide andN-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide), azolidecompounds (e.g., N,N'-carbonyldiimidazole and N,N'-thionyldiimidazole)and the like. When these condensing agents are used, the reaction isconsidered to proceed via a reactive derivative of carboxylic acid.

Production Method 4

Compound (VI) and compound (VII) are reacted.

This method produces a compound of the formula (I) wherein R⁶ is --NR⁷R⁸.

This reaction generally proceeds in an inert solvent. Examples of theinert solvent include acetone, dioxane, acetonitrile, chloroform,benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate, N,N-dimethylformamide, pyridine, water and the like, andmixtures thereof.

In addition, a base such as triethylamine, pyridine,4-dimethylaminopyridine, potassium carbonate and the like may be added.

The reaction temperature is generally from -10° C. to 160° C.,preferably 10-100° C., and the reaction time is generally from 30minutes to 10 hours.

The starting compound (VI) can be produced, for example, by dissolvingcompound (II) in an inert solvent and bubbling in phosgene.

Production Method 5

Compound (VIII) and compound (IX) are reacted.

This reaction generally proceeds in an inert solvent. Examples of theinert solvent include acetone, dioxane, acetonitrile, chloroform,benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate, N,N-dimethylformamide, pyridine, water and the like, andmixtures thereof.

In addition, a base such as triethylamine, pyridine,4-dimethylaminopyridine, potassium carbonate, sodium hydride and thelike may be added.

The reaction temperature is generally from -10° C. to 100° C.,preferably 0-60° C., and the reaction time is generally from 30 minutesto 10 hours.

The starting compound (VIII) can be prepared, for example, by the methodwherein a nitro group is introduced into a compound of the formula (X)(introduction of nitro onto benzene ring), and the nitro group isreduced using a catalyst such as palladium-carbon and the like to give acompound of the formula (XI) ##STR7## wherein R¹¹, R¹², R¹³, R¹⁴ and mare as defined above. Using this compound as a starting compound andaccording to Production Method 2, a compound of the formula (XII)##STR8## wherein R¹, R², R³, R⁴, R¹⁴ and m are as defined above, isobtained. This compound is deprotected to give compound (VIII).

The Compound (I) of the present invention obtained as in the above canbe purified by a method conventionally known, such as chromatography andrecrystallization.

This Compound (I) can be converted to a pharmaceutically acceptable saltby a method known Per se.

The Compound (I) and pharmaceutically acceptable salts thereof of thepresent invention show superior ACAT inhibitory activity andlipoperoxidation inhibitory activity in mammals (e.g., human, cow,horse, dog, cat, rabbit, rat, mouse, hamster and the like) and areuseful as ACAT inhibitors and hyperlipemia inhibitors. To be specific,they are useful for the prevention and treatment of arterioscleroticlesions such as arteriosclerosis, hyperlipemia and diabetes, as well asischemic diseases of brain, heart and the like.

A pharmaceutical composition containing Compound (I) or apharmaceutically acceptable salt thereof of the present invention maycontain an additive. Examples of the additive include excipients (e.g.,starch, lactose, sugar, calcium carbonate and calcium phosphate),binders (e.g., starch, gum arabic, carboxymethylcellulose,hydroxypropylcellulose and crystalline cellulose), lubricants (e.g.,magnesium stearate and talc), disintegrators (e.g., calciumcarboxymethylcellulose and talc), and the like.

The above-mentioned ingredients are mixed, and the mixture can beformulated into an oral preparation such as capsule, tablet, finegranules, granules, dry syrup and the like, or a parenteral preparationsuch as injection, suppository and the like by a method conventionallyknown.

While the dose of Compound (I) and pharmaceutically acceptable saltsthereof of the present invention varies depending on administrationtarget, symptom and other factors, it is generally about 0.1-50 mg/kgbody weight per dose for an adult patient with hypercholesterolemia byoral administration in about one to three times a day.

The present invention is described in more detail in the following byway of Examples, to which the present invention is not limited.

EXAMPLE 1 1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea (1)1-acetyl-4,6-dimethylindoline

4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml), andsodium cyanoborohydride (2.3 g) was added portionwise at 15° C. Themixture was stirred at said temperature for one hour and poured into icewater. Saturated aqueous sodium hydrogencarbonate was added toneutralize the mixture and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in benzene, and acetic anhydride (840 mg) was added, whichwas followed by stirring at room temperature for one hour. The reactionmixture was washed with saturated aqueous sodium hydrogencarbonate andsaturated brine, and dried over sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent:chloroform-methanol=1:0-10:1) to give 1.3 g of the title compound (1).

¹ H-NMR (CDCl₃) δ:

2.18 (6H, s, --CH₃, --COCH₃), 2.30 (3H, s, --CH₃),

3.00 (2H, t, J=8.3Hz, C₃ --H₂), 4.03 (2H, t, J=8.3Hz, C₂ --H₂),

6.66 (1H, s, C₅ --H), 7.89 (1H, S, C₇ --H)

(2) 1-acetyl-4,6-dimethyl-5-nitroindoline

1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride(35 ml), and nitric acid (d=1.5, 0.92 ml) dissolved in acetic anhydride(15 ml) was added dropwise at 0° C. The mixture was stirred at roomtemperature for one hour and poured into ice water. Saturated aqueoussodium hydrogencarbonate was added to neutralize the mixture, and themixture was extracted with chloroform. The extract was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent :chloroform-methanol=1:0-100:1) to give 2.4 g of the title compound (2).

¹ H-NMR (CDCl₃) δ:

2.17 (3H, s, --COCH₃), 2.24 (3H, s, --CH₃),

2.30 (3H, s, --CH₃), 3.08 (2H, t, J=8.4Hz, C₃ --H₂),

4.14 (2H, t, J=8.3Hz, C₂ --H₂), 8.00 (1H, S, C₇ --H)

(3) 4,6-dimethyl-1-hexyl-5-nitroindoline

1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) obtained in (2) wasdissolved in methanol.(25 ml) and 6N hydrochloric acid (20 ml) wasadded, which was followed by refluxing for 15 hours. After thecompletion of the reaction, the solvent was evaporated under reducedpressure. The residue was dissolved in chloroform, and the mixture waswashed with saturated aqueous sodium hydrogencarbonate and saturatedbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure. Indoline (1.8 g) thus obtained was dissolved indimethylformamide (20 ml), and sodium hydride (abt. 60% in oilsuspension, 457 mg) was added at 0° C. The mixture was stirred at saidtemperature for 0.5 hour and hexyl bromide (1.8 g) was added to thereaction mixture, which was followed by stirring at room temperature for3 hours. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: hexane-ethyl acetate=1:0 -10:1) togive 2.8 g of the title compound (3).

¹ H-NMR (CDCl₃) δ:

0.90 (3H, br-t, --CH₃), 1.2-1.8 (8H, m, --(CH₂)₄ --),

2.17 (3H, s, --CH₃), 2.30 (3H, s, --CH₃),

3.00 (2H, t, J=8.4Hz, C₃ --H₂), 3.09 (2H, t, J=7.2Hz, N--CH₂),

3.51 (2H, t, J=8.3Hz, C₂ --H₂), 5.99 (1H, s, C₇ --H)

(4) 1-butyl-3-(1-hexyl-4,6-dimethylindolin-5-yl)urea

4,6-Dimethyl-1-hexyl-5-nitroindoline (1.0 g) obtained in (3) wasdissolved in benzene (40 ml) and 10% palladium-carbon (100 mg) was addedto allow hydrogenation at 40° C. After the completion of the reaction,palladium-carbon was filtered off, and the filtrate was washed withsaturated aqueous sodium hydrogencarbonate and saturated brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure. 5-Amino-4,6-dimethyl-1-hexylindoline thus obtained wasdissolved in chloroform (20 ml) and butyl isocyanate (400 mg) was addedto the reaction mixture, which was followed by stirring at roomtemperature for 18 hours. Water was added to the reaction mixture, andthe mixture was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (developing solvent:chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give650 mg of the title compound (4).

¹ H-NMR (CDCl₃) δ:

0.91 (6H, br-t, --CH₃),

1.0-2.0 (12H, m, --(CH₂)4-, --(CH₂)₂ --),

2.09 (3H, s, --CH₃), 2.19 (3H, s, --CH₃),

2.6-3.6 (8H, m, CO--CH₂, C₃ --H₂, N--CH₂, C₂ --H₂),

4.29 (1H, br, NH), 5.45 (1H, br, NH),

6.18 (1H, S, C₇ --H)

EXAMPLE 2 N-(1-hexyl-4,6-dimethylindolin-5-yl)-2,2-dimethylpropanamide

5-Amino-4,6-dimethyl-1-hexylindoline (880 mg) was dissolved inchloroform (20 ml), and triethylamine (370 mg) and pivaloyl chloride(430 mg) were added, which was followed by stirring at room temperaturefor 1 hour. Water was added to the reaction mixture, and the mixture waswashed with saturated brine and dried over sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (developing solventchloroform-methanol=1:0-50:1) and recrystallized from ethanol to give650 mg of the title compound.

¹ H-NMR (CDCl₃) δ:

0.84 (3H, br-t, -CH₃), 1.1-1.8 (8H, m, --(CH₂)₄ --),

1.33 (9H, s, -(CH₃)₃), 2.00 (3H, s, --CH₃),

2.11 (3H, s, -CH₃), 2.82 (2H, t, J=7.8Hz, C₃ --H₂),

2.99 (2H, t, J=7.2Hz, N--CH₂), 3.33 (2H, t, J=7.8Hz, C₂ --H₂),

6.16 (1H, s, C₇ --H), 6.70 (1H, br, N--H)

EXAMPLE 3 N-(1-hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide(1) 1-acetyl-5-bromo-4,6-dimethylindoline

1-Acetyl-4,6-dimethylindoline (5.5 g) was dissolved in acetic acid (150ml), and bromine (2.2 ml) was added dropwise at room temperature. Themixture was stirred at room temperature for 1 hour, and poured into icewater. The precipitated solid was collected by filtration, andrecrystallized from methanol to give 6.5 g of the title compound (1).

¹ H-NMR (CDC13) δ:

2.19 (3H, s, --COCH₃), 2.27 (3H, s, --CH₃),

2.39 (3H, s, --CH₃), 3.06 (2H, t, J=8.4Hz, C₃ --H₂),

4.03 (2H, t, J=8.4Hz, C₂ --H₂), 7.99 (1H, S, C₇ --H)

(2) 5-bromo-4,6-dimethyl-7-nitroindoline

Concentrated sulfuric acid (25 ml) and nitric acid (d=1.56, 1.46 ml)were added to acetic acid (25 ml), and1-acetyl-5-bromo-4,6-dimethylindoline (6.5 g) obtained in (1) was addedwhile stirring the mixture at 0° C., which was followed by stirring atsaid temperature for 18 hours. The reaction mixture was poured into icewater, and the precipitated solid was collected by filtration and washedthoroughly with water. The obtained solid was suspended in ethanol (50ml) and water (10 ml). Sodium hydroxide (20 g) was added and the mixturewas refluxed for 3 hours. The solvent was evaporated under reducedpressure and chloroform was added. The mixture was washed with saturatedbrine and dried over sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent : benzene) to give 4.8 g of the titlecompound (2).

¹ H-NMR (CDCl₃) δ:

2.29 (3H, s, C₄ --CH₃), 2.65 (3H, s, C₆ --CH₃),

3.10 (2H, t, J=8.4Hz, C₃ --H₂), 3.82 (2H, t, J=8.4Hz, C₂ --H₂),

9.0 (1H, br, N--H)

(3) N- (l -hexyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide

5-Bromo-4,6-dimethyl-7-nitroindoline (3.0 g) obtained in (2) wasdissolved in dimethylformamide (60 ml) and sodium hydride (abt. 60% inoil suspension, 530 mg) was added at 0° C., which was followed bystirring at said temperature for 0.5 hour. Hexyl bromide (1.8 g) wasadded to the reaction mixture and the mixture was stirred at roomtemperature for 12 hours. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine and dried over sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent: hexane-ethylacetate=1:0-10:1). The obtained solid was dissolved in benzene (40 ml)and 10% palladium-carbon (100 mg) was added to allow hydrogenation at40° C. After the completion of the reaction, palladium-carbon wasfiltered off, and the filtrate was washed with saturated aqueous sodiumhydrogencarbonate and saturated brine, and dried over sodium sulfate.The solvent was evaporated under reduced pressure.

7-Amino-4,6-dimethyl-1-hexylindoline thus obtained was dissolved inchloroform (20 ml), and triethylamine (1.0 g) and pivaloyl chloride (1.0g) were added to the reaction mixture, which was followed by stirring atroom temperature for 1 hour. Water was added to the reaction mixture,and the mixture was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (developing solvent :chloroform-methanol=1:0-50:1). The obtained compound (3) was dissolvedin ethanol and 1ON hydrochloric acid/ethanol (1 ml) was added. Thesolvent was evaporated under reduced pressure. The residue wasrecrystallized from ethanol to give 700 mg of hydrochloride of the titlecompound (3).

¹ H-NMR (CDCl₃) δ:

0.90 (3H, br-t, --CH₃), 1.1-1.6 (8H, m, --(CH₂)₄ --),

1.41 (9H, s, --(CH₃)₃), 2.15 (3H, s, --CH₃),

2.25 (3H, s, --CH₃), 3.15 (4H, m, C₃ --H₂, N--CH₂),

3.70 (1H, m, C₂ --H), 4.00 (1H, m, C₂ --H),

7.12 (1H, s, C₅ --H), 9.2 (1H, br, N--H)

EXAMPLE 4 1-butyl-3-(1-hexyl-4,6-dimethylindolin-7-yl)urea

7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved inchloroform (20 ml) and butyl isocyanate (400 mg) was added, which wasfollowed by stirring at room temperature for 18 hours. Water was addedto the reaction mixture, and the mixture was washed with saturated brineand dried over sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent : chloroform-methanol=1:0-50:1) and recrystallizedfrom ethanol to give 450 mg of the title compound.

¹ H-NMR (CDCl₃) 8 :

0.88 (6H, br-t, --CH₃),

1.0-1.8 (12H, m, --(CH₂)₄ --, --(CH₂)₂ --),

2.13 (6H, s, --CH₃ X₂), 2.83 (2H, t, J=8.3Hz, C₃ --H₂),

3.20 (4H, N--CH₂ X₂), 3.43 (2H, t, J=8.3Hz, C₂ --H₂),

4.80 (1H, br-t, NH--CH₂), 5.52 (1H, br-s, C₇ --NH),

6.40 (1H, s, Cs--H)

EXAMPLES 5-36

In the same manner as in any one of the above-mentioned Examples 1-4,the compounds shown in Tables 1 and 2 were obtained.

                                      TABLE 1                                     __________________________________________________________________________      #STR9##                                                                        -                                                                          Example                                                                            R.sup.1                                                                             R.sup.2                                                                          R.sup.3                                                                             R.sup.6     R.sup.5                                       __________________________________________________________________________     5   --H   --H                                                                              --CH.sub.3                                                                          --C(CH.sub.3).sub.3                                                                       --(CH.sub.2).sub.5 CH.sub.2                      6 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.8                                           CH.sub.3 --CH.sub.2 CH.sub.3                     7 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5                                       CH.sub.3                                         8 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3                                         CH.sub.3                                         9 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                           CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3                                           10 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3                                    ).sub.2 (CH.sub.2).sub.5 CH.sub.3                                             --(CH.sub.2).sub.3 CH.sub.3                     11 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.7                                         CH.sub.3                                        12 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3                                         13 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3                                    ).sub.2 (CH.sub.2).sub.5 CH.sub.3                                             --CH.sub.2 CH.sub.3                             14 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                           CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3                                           15 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3                                    ).sub.2 (CH.sub.2).sub.5 CH.sub.3                                             --(CH.sub.2).sub.5 CH.sub.3                     16 --CH.sub.3 --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3                                          17 --CH.sub.3 --H --CH.sub.3 --CH(CH.sub.                                    3).sub.2 --(CH.sub.2).sub.5 CH.sub.3                                           18 --CH.sub.3 --H --CH.sub.3 --CH.sub.2                                      C(CH.sub.3).sub.2 CH.sub.2 COOH --(CH.sub.                                    2).sub.5 CH.sub.3                               19 --CH.sub.2 CH.sub.3 --H --CH.sub.2 CH.sub.3 --C(CH.sub.3).sub.3                                          --(CH.sub.2).sub.5 CH.sub.3                     20 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.2 COOH                                      --(CH.sub.2).sub.5 CH.sub.3                   __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________      #STR10##                                                                       -                                                                          Example                                                                            R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                           R.sup.8          R.sup.5                                      __________________________________________________________________________    21   --CH.sub.3                                                                        --H                                                                              --CH.sub.3                                                                        --(CH.sub.2).sub.3 CH.sub.3                                                                    --(CH.sub.2).sub.5 CH.sub.3                    22 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.2                                          OCOCH.sub.3                                    23 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.2                                          OCH.sub.3                                      24 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.2                                          OC.sub.2 H.sub.5                               25 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --C.sub.5 H.sub.11                                           26 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.                                     3).sub.3 --(CH.sub.2).sub.5 COOH                                               27 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.                                     3).sub.3 --C.sub.7 H.sub.15                    28 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OH --C.sub.6                                       H.sub.13                                       29 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OCOCH.sub.3                                        --C.sub.6 H.sub.13                              - 30 --CH.sub.3 --H --CH.sub.3                                                                                --C.sub.6 H.sub.13                            - 31 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.2                                       CH(CH.sub.3).sub.2                             32 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2 CH(CH.sub.3)                                     .sub.2                                          - 33 --CH.sub.3 --H --CH.sub.3                                                                                --C.sub.6 H.sub.13                            - 34 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OC.sub.2                                        H.sub.5 --C.sub.6 H.sub.13                      - 35 --CH.sub.3 --H --CH.sub.3                                                                                --C.sub.6 H.sub.13                            - 36 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --C.sub.3 H.sub.7       __________________________________________________________________________

The ¹ H-NMR data of the compounds of the above Examples 5-36 are shownin the following.

¹ H-NMR (CDCl₃) δ:

EXAMPLE 5

(hydrochloride) 0.91 (3H, br-t), 1.1-1.8 (8H, m), 1.34 (9H, s), 2.09(3H, s), 2.93-3.48 (4H, m), 3.48-3.82 (1H, m), 3.82-4.35 (1H, m), 7.12(1H, d), 7.32 (1H, d), 9.36 (1H, br-s)

EXAMPLE 6

0.93 (3H, br-t), 1.0-2.0 (19H, m), 1.35 (6H, s), 2.12 (3H, s), 2.19 (3H,s), 2.98 (2H, t), 3.25 (2H, t), 3.65 (2H, t), 6.80 (1H, s), 8.09 (1H,br-s)

EXAMPLE 7

0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.31 (9H, s), 2.84 (2H, t), 3.16 (2H,t), 3.44 (2H, t), 3.74 (3H, s), 3.79 (3H, s), 5.86 (1H, s)

EXAMPLE 8

0.92 (3H, br-t), 1.39 (9H, s), 1.2-1.9 (4H, m), 2.08 (3H, s), 2.15 (3H,s), 2.80-3.30 (4H, m), 3.60 (2H, t), 6.68 (1H, s), 7.78 (1H, br-s)

EXAMPLE 9

0.90 (3H, br-t), 0.92 (3H, br-t), 1.08-1.88 (1OH, m), 1.29 (6H, s), 2.05(3H, s), 2.12 (3H, s), 2.81 (2H, t), 3.13 (2H, t), 3.40 (2H, t), 6.39(1H, s), 6.74 (1H, br-s)

EXAMPLE 10

0.63-1.05 (6H, m), 1.05-1.82 (14H, m), 1.29 (6H, s), 2.08 (3H, s), 2.10(3H, s), 2.82 (2H, s), 3.13 (2H, t), 3.41 (2H, t), 6.41 (1H, s), 6.77(1H, br-s)

EXAMPLE 11

0.88 (3H, br-t), 1.01-1.87 (12H, m), 1.35 (9H, s), 2.09 (3H, s), 2.14(3H, s), 2.82 (2H, t), 3.13 (2H, t), 3.52 (2H, t), 6.60 (1H, br-s)

EXAMPLE 12

1.18 (3H, t), 1.35 (9H, s), 2.09 (3H, s), 2.15 (3H, s), 2.92 (2H, t),3.22 (2H, q), 3.56 (2H, t), 6.62 (1H, s), 7.57 (1H, br-s)

EXAMPLE 13

0.88 (3H, br-t), 1.08 (3H, t), 1.29 (6H, s), 1.1-1.9 (10 H, m), 2.08(3H, s), 2.22 (3H, s), 2.82 (2H, t), 3.21 (2H, q), 3.33 (2H, t), 6.43(1H, s), 6.84 (1H, br-s)

EXAMPLE 14

0.90 (3H, br-t), 0.92 (3H, br-t), 1.08-1.88 (14H, m), 1.29 (6H, s), 2.05(3H, s), 2.12 (3H, s), 2.81 (2H, t), 3.13 (2H, t), 3.40 (2H, t), 6.39(1H, s), 6.74 (1H, br-s)

EXAMPLE 15

0.63-1.05 (6H, m), 1.05-1.82 (18H, m), 1.34 (6H, s), 2.11 (3H, s), 2.17(3H, s), 2.95 (2H, s), 3.13 (2H, t), 3.60 (2H, t), 6.72 (1H, s), 7.8(1H, br)

EXAMPLE 16

0.89 (3H, br-t), 1.05-1.70 (8H, m), 1.81 (3H, s), 2.11 (3H, s), 2.15(3H, s), 2.81 (2H, br-t), 2.6-3.8 (4H, m), 6.39 (1H, s), 6.58 (1H, br),6.72 (1H, br)

EXAMPLE 17

0.87 (3H, br-t), 1.05-1.90 (8H, m), 1.25 (3H, s), 1.32 (3H, s), 2.11(3H, s), 2.17 (3H, s), 2.67 (1H, m), 2.7-3.4 (4H, m), 3.59 (2H, t), 6.69(1H, s), 7.83 (1H, br-s)

EXAMPLE 18

0.87 (3H, br-t), 1.05-1.80 (8H, m), 1.21 (6H, s), 2.17 (6H, s), 2.48(2H, s), 2.55 (2H, s), 3.01 (2H, t), 3.10 (2H, t), 3.54 (2H, t), 6.70(1H, s), 6.8-8.2 (1H, br-s), 8.72 (1H, br-s)

EXAMPLE 19

0.87 (3H, br-t), 1.05-1.80 (8H, m), 1.17 (3H, t), 1.20 (3H, t), 1.35(9H, s), 2.22-2.62 (4H, m), 2.91 (2H, t), 3.04 (2H, t), 3.48 (2H, br-t),6.56 (1H, s), 7.25 (1H, br-s)

EXAMPLE 20

0.85 (3H, br-t), 1.05-1.80 (8H, m), 1.27 (6H, s), 1.80-2.25 (2H, m),2.10 (3H, s), 2.16 (3H, s), 2.25-2.55 (2H, m), 2.90 (2H, t), 3.04 (2H,t), 3.47 (2H, t), 6.69 (1H, s), 8.49 (1H, br-s), 8.95 (1H, br-s)

EXAMPLE 21

0.83 (3H, br-t), 0.87 (3H, br-t), 1.1-1.8 (11H, m), 2.11 (3H, s), 2.16(3H, s), 2.29 (1H, t), 2.85 (2H, t), 3.22 (2H, t), 3.55 (2H, t), 6.49(1H, s), 6.68 (1H, br)

EXAMPLE 22

1.27 (9H, s), 2.04 (6H, s), 2.13 (3H, s), 3.06 (2H, t), 3.43 (2H, t),3.75 (2H, t), 4.29 (2H, t), 6.87 (1H, s), 9.15 (1H, br-s)

EXAMPLE 23

1.33 (9H, s), 2.04 (3H, s), 2.09 (3H, s), 2.8-2.9 (4H, m), 3.38 (3H, s),3.4-3.6 (4H, m), 6.36 (1H, s), 7.35 (1H, br-s)

EXAMPLE 24

1.16 (3H, t), 1.32 (9H, s), 2.04 (3H, s), 2.09 (3H, s), 2.82 (2H, t),3.3-3.6 (8H, m), 6.53 (1H, s), 7.40 (1H, br-s)

EXAMPLE 25

0.88 (3H, br-t), 1.35 (9H, s), 1.2-1.9 (6H, m), 2.08 (3H, s), 2.15 (3H,s), 2.92 (2H, t), 3.13 (2H, t), 3.55 (2H, t), 6.23 (1H, s), 7.60 (1H,br-s)

EXAMPLE 26

1.1-1.9 (6H, m), 1.39 (9H, s), 2.07 (3H, s), 2.13 (3H, s), 2.29 (2H, t),2.84 (2H, t), 3.11 (2H, t), 3.43 (2H, t), 5.40 (1H, br), 6.52 (1H, s),7.30 (1H, br-s)

EXAMPLE 27

0.87 (3H, br-t), 1.1-1.8 (1OH, m), 1.34 (9H, s), 2.07 (3H, s), 2.13 (3H,s), 2.87 (2H, t), 3.13 (2H, t), 3.49 (2H, t), 6.52 (1H, s), 7.20 (1H,br-s)

EXAMPLE 28

0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.26 (6H, s), 1.99 (3H, s), 2.08 (3H,s), 2.78 (2H, t), 3.10 (2H, t), 3.37 (2H, t), 3.48 (2H, s), 4.00 (1H,br-s), 6.35 (1H, s), 7.81 (1H, s)

EXAMPLE 29

0.87 (3H, br-t), 1.1-1.8 (8H, m), 1.28 (6H, s), 2.07 (6H, s), 2.12 (3H,s), 2.84 (2H, t), 3.14 (2H, t), 3.43 (2H, t), 4.20 (2H, s), 6.48 (1H,s), 7.35 (1H, s)

EXAMPLE 30

0.87 (3H, br-t), 1.1-1.8 (8H, m), 2.15 (6H, s), 2.82 (2H, t), 3.16 (2H,t), 3.43 (2H, t), 6.43 (1H, s), 7.42 (2H, m), 8.22 (1H, m), 8.75 (1H,m), 9.16 (1H, br-s)

EXAMPLE 31

0.90 (6H, d), 1.3-1.8 (3H, m), 1.36 (9H, s), 2.09 (3H, s), 2.16 (3H, s),2.92 (2H, t), 3.16 (2H, t), 3.54 (2H, t), 6.65 (1H, s), 7.65 (1H, br-s)

EXAMPLE 32

0.94 (6H, d), 1.33 (9H, s), 1.7-2.0 (1H, m), 2.04 (3H, s), 2.10 (3H, s),2.82 (2H, t), 2.94 (2H, t), 3.38 (2H, t), 6.37 (1H, s), 6.70 (1H, br-s)

EXAMPLE 33

0.85 (3H, br-t), 1.1-1.8 (8H, m), 1.44 (6H, S), 2.03 (3H, s), 2.08 (3H,s), 2.80 (2H, t), 3.14 (2H, t), 3.41 (2H, t), 4.50 (2H, s), 6.37 (1H,s), 7.04 (1H, br-s), 7.40 (2H, m), 8.28 (1H, m), 8.75 (1H, m), 9.21 (1H,d)

EXAMPLE 34

0.88 (3H, br-t), 1.1-1.8 (8H, m), 1.23 (3H, t), 1.27 (6H, s), 2.07 (3H,s), 2.10 (3H, s), 2.81 (2H, t), 3.18 (2H, t), 3.41 (2H , t), 3.48 (2H,s), 3.55 (2H, q), 6.37 (1H, s), 8.00 (1H, br-s)

EXAMPLE 35

0.88 (3H, br-t), 1.1-1.8 (14H, m), 1.24 (6H, s), 2.10 (6H, s), 2.50 (2H,t), 2.90 (2H, t), 2.8-3.6 (8H, m), 6.39 (1H, s), 7.00 (1H, br-s)

EXAMPLE 36

0.87 (3H, br-t), 1.2-1.9 (2H, m), 1.35 (9H, s), 2.08 (3H, s). 2.15 (3H,s), 2.93 (2H, t), 3.12 (2H, t), 3.50 (2H, t), 6.30 (1H, s), 7.40 (1H,br-s)

In the same anner as in any one of the above-mentioned Examples 1-4, thecompounds shown in Tables 3 to 9 can be obtained.

                                      TABLE 3                                     __________________________________________________________________________      #STR14##                                                                       -                                                                          Example                                                                            R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                           R.sup.6           R.sup.5                                     __________________________________________________________________________    37   --CH.sub.3                                                                        --H                                                                              --CH.sub.3                                                                        --C(CH.sub.3).sub.3                                                                             --CH.sub.2 --CH═C(CH.sub.3).sub.2                                          38 --CH.sub.3 --H --CH.sub.3 --C(CH.sub                                      .3).sub.3 --(CH.sub.2).sub.4 SO.sub.3                                         Na                                             - 39 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3                                                             #STR15##                                     - 40 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3                                                             #STR16##                                     - 41 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3                                                             #STR17##                                     - 42 --CH.sub.3 --H --CH.sub.3                                                                                 --CH.sub.2 CH.sub.3                          - 43 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.3 CH.sub.3                  - 44 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 CH.sub.3                  - 45 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 COOH                      - 46 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 CH.sub.3                  - 47 --CH.sub.3 --H --CH.sub.3                                                                                 (CH.sub.2).sub.5 CH.sub.3                    - 48 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 CH.sub.3                  - 49 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 CH.sub.3                  - 50 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.5 CH.sub.3                  - 51 --CH.sub.3 --H --CH.sub.3                                                                                 --CH.sub.2 CH.sub.3                          - 52 --CH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.4 OC(CH.sub.3).sub.3                                         (CH.sub.2).sub.3 CH.sub.3                      - 53 --CH.sub.3 --H --CH.sub.3                                                                                 --(CH.sub.2).sub.3 CH.sub.3               __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________      #STR29##                                                                       -                                                                          Example                                                                            R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                              R.sup.6               R.sup.5                              __________________________________________________________________________      54 --CH.sub.3 --H --CH.sub.3                                                                                           --CH.sub.2 CH.sub.3                   - 55 --CH.sub.3 --H --CH.sub.3                                                                                        --CH.sub.2 CH.sub.3                   - 56 --CH.sub.3 --H --CH.sub.3                                                                                        --CH.sub.2 CH.sub.3                   - 57 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.3 --(CH.sub.2                                             ).sub.5 CH.sub.3                       58 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.2                                                    SO.sub.3 Na --(CH.sub.2).sub.5                                                CH.sub.3                               59 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.2 (CH.sub.2).sub                                             .2 SO.sub.3 Na --(CH.sub.2).sub.5                                              CH.sub.3                               - 60 --CH.sub.3 --H --CH.sub.3                                                                                        --(CH.sub.2).sub.5 CH.sub.3                                                   - 61 --CH.sub.3 --H --CH.sub.3                                                --(CH.sub.2).sub.5 CH.sub.3                                                   - 62 --H --H --OCH.sub.3                                                    --C(CH.sub.3).sub.3 --(CH.sub.2).                                             sub.6 CH.sub.3                         63 --H --H --OCH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.4 CH.sub.3                                                64 --H --H --OCH(CH.sub.3).sub.2                                              --C(CH.sub.3).sub.3 --(CH.sub.2)                                             .sub.5 CH.sub.3                        65 --H --H --OCH(CH.sub.3).sub.2 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.4                                              CH.sub.3                               66 --H --H --OCH(CH.sub.3).sub.2 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2                                             ).sub.5 CH.sub.3                       67 --H --H --OCH(CH.sub.3).sub.2 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2                                             ).sub.5 CH.sub.3                     __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________      #STR35##                                                                       -                                                                          Example                                                                             R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                           --R.sup.6 --R.sup.5 --                                      __________________________________________________________________________    68    --CH.sub.3                                                                        --H --CH.sub.3                                                                        --C(CH.sub.3).sub.2 (CH.sub.2).sub.2 --                       69 --CH.sub.3 --H --CH.sub.3 --CH.sub.2 C(CH.sub.3).sub.2 (CH.sub.2).sub                      .2 --                                                         70 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OCO(CH.sub.2).                      sub.3 --                                                      71 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OCOC(CH.sub.3)                      .sub.2 (CH.sub.2).sub.3 --                                  __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________      #STR36##                                                                       -                                                                          Example                                                                            R.sup.1                                                                             R.sup.2                                                                          R.sup.3                                                                             R.sup.7  R.sup.5                                          __________________________________________________________________________    72   --H   --H                                                                              --CH.sub.3                                                                          --C(CH.sub.3).sub.3                                                                    --(CH.sub.2).sub.5 CH.sub.3                         - 73 --CH.sub.3 --H --CH.sub.3                                                                            --(CH.sub.2).sub.5 CH.sub.3                       - 74 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5                                  CH.sub.3                                          75 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3                                      CH.sub.3                                            - 76 --CH.sub.3 --H --CH.sub.3                                                                            --(CH.sub.2).sub.3 CH.sub.3                       - 77 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.7                                   CH.sub.3                                           78 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3                                       - 79 --CH.sub.3 --H --CH.sub.3                                                --CH.sub.2 CH.sub.3                               - 80 --CH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2)                                 .sub.5 CH.sub.3                                    81 --H --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3                  82 --H --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.5                                     CH.sub.3                                           83 --H --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).sub.5                                     CH.sub.3                                           84 --H --H --CH.sub.3 --CH.sub.3 --(CH.sub.2).sub.7 CH.sub.3                  85 --H --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.7                                     CH.sub.3                                           86 --H --H --CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).sub.7                                     CH.sub.3                                           87 --H --H --OCH.sub.3 --CH.sub.3 --CH.sub.2 CH.sub.3                         88 --H --H --OCH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --CH.sub.2 CH.sub.3                                    89 --H --H --OCH.sub.3 --(CH.sub.2).sub.5                                    CH.sub.3 --CH.sub.2 CH.sub.3                       90 --H --H --OCH.sub.3 --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3                 91 --H --H --OCH.sub.3 --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.3                                    CH.sub.3                                           92 --H --H --OCH.sub.3 --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).sub.3                                    CH.sub.3                                         __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________      #STR40##                                                                       -                                                                          Example                                                                            R.sup.1                                                                            R.sup.3                                                                            R.sup.4                                                                           R.sup.7   R.sup.5                                          __________________________________________________________________________    93   --H  --CH.sub.3                                                                         --H --C(CH.sub.3).sub.3                                                                     --(CH.sub.2).sub.5 CH.sub.3                        94 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                        CH.sub.3 --(CH.sub.2).sub.5 CH.sub.3                                           95 --OCH.sub.3 --OCH.sub.3 --H --C(CH.sub.3)                                 .sub.3 --(CH.sub.2).sub.5 CH.sub.3                 96 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3                                      CH.sub.3                                           97 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                        CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3                                           98 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).s                                 ub.2 (CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).s                                 ub.3 CH.sub.3                                      99 --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3 --(CH.sub.2).sub.7                                      CH.sub.3                                           100  --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3                                    101  --CH.sub.3 --CH.sub.3 --H --C(CH.sub.3)                                 .sub.2 (CH.sub.2).sub.5 CH.sub.3 --CH.sub.2                                   CH.sub.3                                           102  --CH.sub.3 --CH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).                                 sub.5 CH.sub.3                                     103  --CH.sub.3 --CH.sub.3 --H --(CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).                                 sub.5 CH.sub.3                                   __________________________________________________________________________

                  TABLE 8                                                         ______________________________________                                          #STR41##                                                                      Example  R.sup.1                                                                              R.sup.3                                                                              R.sup.4                                                                            R.sup.6  R.sup.5                                ______________________________________                                        104    --H    --OCH.sub.3                                                                            --H  --CH.sub.3                                                                             --CH.sub.2 CH.sub.3                        105 --H --OCH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3 --CH.sub.2 CH.sub.3       106 --H --OCH.sub.3 --H --(CH.sub.2).sub.5 CH.sub.3 --CH.sub.2 CH.sub.3       107 --H --OCH.sub.3 --H --CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3                108 --H --OCH.sub.3 --H --(CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).sub.3                                           CH.sub.3                                 ______________________________________                                    

                                      TABLE 9                                     __________________________________________________________________________      #STR42##                                                                       -                                                                          Example                                                                            R.sup.1                                                                            R.sup.2                                                                          R.sup.3                                                                             R.sup.6   R.sup.5                                          __________________________________________________________________________    109  --CH.sub.3                                                                         --H                                                                              --CH.sub.3                                                                          --C(CH.sub.3).sub.3                                                                     --(CH.sub.2).sub.5 CH.sub.3                        110 --H --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5 CH.sub.3                                    111 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).                                 sub.2 (CH.sub.2).sub.3 CH.sub.3 --(CH.sub.2).                                 sub.5 CH.sub.3                                     112 --OCH.sub.3 --H --OCH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.5                                   CH.sub.3                                           113 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.3                                     CH.sub.3                                           114 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.2 (CH.sub.2).sub.3                                       CH.sub.3 --(CH.sub.2).sub.3 CH.sub.3                                           115 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).                                 sub.2 (CH.sub.2).sub.5 CH.sub.3 --(CH.sub.2).                                 sub.3 CH.sub.3                                     116 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --(CH.sub.2).sub.7                                     CH.sub.3                                           117 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).sub.3 --CH.sub.2 CH.sub.3                                     118 --CH.sub.3 --H --CH.sub.3 --C(CH.sub.3).                                 sub.2 (CH.sub.2).sub.5 CH.sub.3 --CH.sub.2                                    CH.sub.3                                         __________________________________________________________________________

Experimental Example 1 ACAT inhibitory activity

A high cholesterol feed [a feed added with cholesterol (1%), Clea Japan,Inc.] was fed to male Japanese white rabbits weighing 2-2.5 kg at 100 gper day and the rabbits were bred for 4 weeks. The rabbits were killedby bleeding under anesthesia and small intestine was removed. The mucousmembrane of small intestine was peeled, collected and homogenated. Thehomogenate was centrifuged at 4° C. and 10,000 rpm for 15 min. Theobtained supernatant was further centrifuged at 4° C. and 41,000 rpm for30 minutes to give microsomal fractions. Using this microsomalsuspension as an enzyme sample, dimethyl sulfoxide (DMSO, 5 μl) or atest compound dissolved in DMSO (test compound solution, 5 μl), and areaction substrate [1-¹⁴ C]-oleoyl CoA were added to a reaction buffer.After incubation at 37° C. for 5 minutes, a chloroform-methanol mixturewas added to stop the reaction. Water was added thereto and mixed, andchloroform layer was separated. The solvent was evaporated to dryness,and the residue was dissolved in hexane. The mixture was subjected tothin layer chromatography using a silica gel plate. The spots ofcholesteryl oleate on the silica gel plate were scraped, andquantitatively assayed on a liquid scintillation counter. The ACATinhibitory activity of the test compound was expressed as a proportion(%) of inhibition of cholesteryl oleate, namely, the proportion ofinhibition of cholesteryl oleate production as compared to control.

The results are shown in Tables 10-11.

Experimental Example 2 serum total cholesterol reducing effect

Male Wister rats weighing 180-200 g were bred under free access to ahigh cholesterol feed [added with cholesterol (1%), cholic acid (0.5%)and coconut oil (10%), Clea Japan, Inc.] for 3 days, during which perioda test compound (10-100 mg/kg) suspended in 5% gum arabic solution wasforcibly administered once a day orally for 3 days. Only 5% gum arabicsolution was administered to control animals. After finaladministration, the test animals were fasted for 5 hours and the bloodwas taken. The serum total cholesterol level was determined using acommercially available assay kit (cholesterol-E-Test Wako, Wako PureChemical Industries, Ltd.). The activity of the test compound wasexpressed as a proportion (%) of reduction of serum total cholesterollevel, namely, the proportion of reduction of serum total cholesterol ascompared to control.

The results are shown in Tables 10-11.

Experimental Example 3 LDL peroxidation inhibitory effect

Male Japanese white rabbits weighing 2-2.5 kg were bred on 100 g per dayof a high cholesterol feed [added with cholesterol (1%), Clea Japan,Inc.] for 4 weeks. The blood was taken from carotid and plasma wasobtained. Then, LDL was fractionated from the plasma byultracentrifugation, dialyzed for one day and preserved at 4° C. LDL(400 μg) and aqueous copper sulfate solution (final concentration 5 μM)were added to bufferized Ham F-10 medium (2 ml, GIBCO, USA). DMSO or asolution (20 μl) of test compound dissolved in DMSO was added and themixture was incubated at 37° C. for 24 hours. After the completion ofthe incubation, LDL peroxide in medium was allowed to develop color bythiobarbituric acid method and assayed as malondialdehyde. The activityof the test compound was expressed as malondialdehyde productioninhibitory ratio (%), namely, the proportion of inhibition of productionof malondialdehyde as compared to control.

The results are shown in Tables 10-11.

Experimental Example 4 plasma lipoperoxidation inhibitory effect

The blood was taken from male Japanese white rabbits weighing 2-2.5 kgunder anesthesia and heparinized plasma was separated by a conventionalmethod. To the plasma (2.0 ml) was added DMSO or a solution (20 μl,final concentration 10⁻⁵ M) of test compound dissolved in DMSO, andaqueous copper sulfate solution (final concentration 5 mM) was addedimmediately thereafter. The mixture was incubated at 37° C. for 3 hours.After the completion of the incubation, 20% trichloroacetic acid wasadded to stop the reaction. Then, the mixture was centrifuged at 40° C.,4,500 rpm for 15 minutes. The lipoperoxide in the supernatant thusobtained was assayed as malondialdehyde upon color development bythiobarbituric acid method. The activity of the test compound wasexpressed as malondialdehyde production inhibitory ratio (%), namely,the proportion of inhibition of production of malondialdehyde ascompared to control.

The results are shown in Tables 10-11.

                  TABLE 10                                                        ______________________________________                                                 Result of Result of Result of                                                                             Result of                                   Exp. Ex. 1 Exp. Ex. 2 Exp. Ex. 3 Exp. Ex. 4                                  Test compound (%) *1 (%) *2 (%) *3 (%) *4                                   ______________________________________                                        Example 1                                                                              76.6 **    12.9 *** 99.2    94.3                                       Example 2 59.9 ** -- 99.5 95.8                                                Example 3 97.5 ** 54.4 ** 93.3 90.4                                           Example 4 94.9 ** 21.4 ** 59.5 92.0                                           Example 6 99.8 ** 53.3 ** 24.8 37.4                                           Example 7 96.2 ** 19.2 ** 86.6 86.4                                           Example 8 99.7 ** 48.0 ** 91.9 85.1                                           Example 9 81.3 ** 51.3 ** 93.7 81.6                                           Example 10 98.7 ** 55.2 ** 18.3 82.6                                          Example 11 99.2 ** 59.5 *  91.6 78.8                                          Example 12 71.9 ** 30.3 ** 90.3 74.9                                          Example 13 96.0 ** 28.4 ** 82.4 87.1                                          Example 14 96.6 ** 53.9 ** 88.3 93.1                                          Example 15 93.1 ** 35.0 *  12.3 90.1                                          Example 17 96.7 ** 27.0 *  89.6 91.1                                          Example 18 69.6 *  22.3 ** 34.0 87.1                                          Example 20 22.7 *  7.8 * 67.8 91.1                                            Example 21 94.4 ** 28.3 *  92.1 91.4                                          Example 22 78.5 **  38.6 *** 40.6 92.8                                        Example 23 88.8 ** 23.6 ** 54.8 90.5                                        ______________________________________                                         *1:ACAT inhibition (concentration *: 10.sup.-4 M, **: 10.sup.-5 M)            *2:reduction of serum total cholesterol (dose *: 10 mg/kg/day, **: 30         mg/kg/day, ***: 100 mg/kg/day)                                                *3:LDL peroxidation inhibition (concentration : 10.sup.-5 M)                  *4:plasma lipoperoxidation inhibition (concentration : 10.sup.-5 M)      

                  TABLE 11                                                        ______________________________________                                                 Result of Result of Result of                                                                             Result of                                   Exp. Ex. 1 Exp. Ex. 2 Exp. Ex. 3 Exp. Ex. 4                                  Test compound (%) *1 (%) *2 (%) *3 (%) *4                                   ______________________________________                                        Example 24                                                                             97.1 **   28.3 **   42.2    90.5                                       Example 25 96.8 ** 50.5 ** 92.2 93.1                                          Example 26 26.5 ** 37.4 ** 43.3 90.1                                          Example 27 95.5 **  56.9 *** 92.2 91.1                                        Example 28 79.4 **  20.8 *** 92.2 91.1                                        Example 29 86.6 **  6.9 ** 91.9 91.1                                          Example 30 83.0 **  25.7 *** 94.1 91.8                                        Example 31 93.8 ** 49.0 ** 90.3 90.8                                          Example 32 93.9 ** 57.4 ** 85.3 89.1                                          Example 33 82.2 **  7.2 ** 87.0 89.5                                          Example 34 91.0 ** 50.2 ** 82.9 89.8                                          Example 35 84.6 ** 20.8 ** 71.9 91.4                                          Example 36 95.9 ** 50.2 ** 83.2 89.1                                          YM-750 92.3 ** 43.8 ** 0 --                                                   Probucol  3.4 ** 7.3 * 89.4 87.5                                            ______________________________________                                         *1:ACAT inhibition (concentration *: 10.sup.-4 M, **: 10.sup.-5 M)            *2:reduction of serum total cholesterol (dose *: 10 mg/kg/day, **: 30         mg/kg/day; ***: 100 mg/kg/day)                                                *3:LDL peroxidation inhibition (concentration : 10.sup.-5 M)                  *4:plasma lipoperoxidation inhibition (concentration : 10.sup.-5 M)           YM750:1-cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethyl-phenyl)ure     Probucol:4,4'-isopropylidenedithiobis(2,6di-t-butylphenol)               

Formulation Example 1

Tablets having the following composition are prepared by a conventionalmethod.

    ______________________________________                                        Compound of Example 3                                                                           25 mg                                                         Polyvinylpyrrolidone 20 mg                                                    Starch 75 mg                                                                  Magnesium stearate  2 mg                                                    ______________________________________                                    

Formulation Example 2

Capsules having the following composition are prepared by a conventionalcapsule packing method.

    ______________________________________                                        Compound of Example 6                                                                           100 mg                                                        Lactose  25 mg                                                                Magnesium stearate  1 mg                                                    ______________________________________                                    

The heterocyclic derivative and pharmaceutically acceptable saltsthereof of the present invention show superior ACAT inhibitory activityand lipoperoxidation inhibitory activity, and are useful as ACATinhibitors or hyperlipemia inhibitors. To be specific, they are usefulfor the prevention and treatment of arteriosclerotic lesions such asarteriosclerosis, hyperlipemia and diabetes, as well as ischemicdiseases of brain, heart and the like.

What is claimed is:
 1. A method for inhibiting acyl-CoA:cholesterol acyltransferase in a host in need thereof for the prophylaxis or treatment of arteriosclerosis, diabetes, hyperlipemia, or cerebrovascular or cardiovascular ischemic diseases in said host comprising contacting said host with a heterocyclic compound of the formula (I) ##STR43## wherein one of R¹, R², R³, and R⁴ is a group of the formula --NHCO--R⁶ wherein R⁶ is selected from the group consisting of C₁ -C₁₂ alkyl, cyclo C₃ -C₆ alkyl, cyclo C₃ -C₆ alkyl C₁ -C₃ alkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, naphthyl C₁ -C₄ alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C₁ -C₈ alkyl, piperidyl C₁ -C₈ alkyl, piperidino C₁ -C₈ alkyl, morpholinyl C₁ -C₈ alkyl, morpholino C₁ -C₈ alkyl, piperazinyl C₁ -C₈ alkyl, pyrrolyl C₁ -C₈ alkyl, imidazolyl C₁ -C₈ alkyl, pyridyl C₁ -C₈ alkyl, wherein any of the foregoing is optionally substituted with a C₁ -C₄ alkyl, amino, hydroxy, di(C₁ -C₄)alkylamino, C₁ -C₄ aminoalkyl, C₁ -C₄ alkoxy, carboxyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ carboxyalkyl, C₂ -C₅ acyloxy, phenyl, phenoxy, halogen, or phenyl di (C₁ -C₄) alkylamino, --R^(A) SO₃ A, --R³ PO₃ B where R^(A) and R^(B) are each alkylene and A and B are each alkali metal or hydrogen atom, --NR⁷ R⁸ where R⁷ is selected from the group consisting of C₁ -C₁₂ alkyl, cyclo C₃ -C₆ alkyl, cyclo C₃ -C₆ alkyl C₁ -C₃ alkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, and naphthyl C₁ -C₄ alkyl, wherein any of the foregoing is optionally substituted with a C₁ -C₄ alkyl, amino, hydroxy, di(C₁ -C₄)alkylamino, C₁ -C₄ aminoalkyl, C₁ -C₄ alkoxy, carboxyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ carboxyalkyl, C₂ -C₅ acyloxy, phenyl, phenoxy, halogen, or phenyl (C₁ -C₄)dialkylamino, and R⁸ is hydrogen atom or C₁ -C₄ alkyl, or --R⁹ --OCOR¹⁰ where R⁹ is alkylene and R¹⁰ is selected from the group consisting of C₁ -C₁₂ alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C₁ -C₈ alkyl, piperidyl C₁ -C₈ alkyl, piperidino C₁ -C₈ alkyl, morpholinyl C₁ -C₈ alkyl, morpholino C₁ -C₈ alkyl, piperazinyl C₁ -C₈ alkyl, pyrrolyl C₁ -C₈ alkyl, imidazolyl C₁ -C₈ alkyl, pyridyl C₁ -C₈ alkyl, wherein any of the foregoing is optionally substituted with a C₁ -C₄ alkyl, amino, hydroxy, C₁ -C₄ dialkylamino, C₁ -C₄ aminoalkyl, C₁ -C₄ alkoxy, carboxyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ carboxyalkyl, C₂ -C₅ acyloxy, phenyl, phenoxy, halogen, or phenyl di (C₁ -C₄)alkylamino, and the remaining three of R¹, R² R³, or R⁴ may be the same or different and each is independently a hydrogen atom, a C₁ -C₄ alkyl or a C₁ -C₄ alkoxy; R⁵ is selected from the group consisting of C₁ -C₁₂ alkyl, cyclo C₃ -C₆, alkyl, cyclo C₃ -C₆ alkyl C₁ -C₃ alkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, naphthyl C₁ -C₄ alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C₁ -C₈ alkyl, piperidyl C₁ -C₈ alkyl, piperidino C₁ -C₈ alkyl, morpholinyl C₁ -C₈ alkyl, morpholino C₁ -C₈ alkyl, piperazinyl C₁ -C₈ alkyl, pyrrolyl C₁ -C₈ alkyl, imidazolyl C₁ -C₈ alkyl, pyridyl C₁ -C₈ alkyl, wherein any of the foregoing is optionally substituted with a C₁ -C₈ alkyl, amino, hydroxy, C₁ -C₄ dialkylamino, C₁ -C₄ aminoalkyl, C₁ -C₄ alkoxy, carboxyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ carboxyalkyl, C₂ -C₅ acyloxy, phenyl, phenoxy, halogen, or phenyl di (C₁ -C₄)alkylamino, an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl, --R^(D) SO₃ D or a R^(E) PO₃ E where R^(D) and R^(E) are each alkylene and D and E are each alkali metal or hydrogen atom, and m is 1, or a pharmaceutically acceptable salt thereof, with the proviso that R⁵ is not ethyl when R¹, R³, and R⁴ are hydrogen atom, R² is (4-methylpentanoyl)amino, and m is
 1. 2. The method of claim 1, wherein one of R² and R⁴ is NHCO-R⁶ and the other is hydrogen; R¹ and R³ are both C₁ -C₄ alkyl or both C₁ -C₄ alkoxy; when R⁵ is unsubstituted C₁ -C₁₂ alkyl, R⁶ is C₁ -C₁₂ alkyl which is optionally substituted with hydroxy, C₂ -C₅ acyloxy, or C₁ -C₄ alkoxy, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C₁ -C₈ alkyl, piperidyl C₁ -C₈ alkyl, piperidino C₁ -C₈ alkyl, morpholinyl C₁ -C₈ alkyl, morpholino C₁ -C₈ alkyl, piperazinyl C₁ -C₈ alkyl, pyrrolyl C₁ -C₈ alkyl, imidazolyl C₁ -C₈ alkyl, pyridyl C₁ -C₈ alkyl, --NR⁷ R⁸ wherein R⁷ is hydrogen, and R⁸ is C₁ -C₁₂ alkyl, or --R⁹ --OCOR¹⁰, wherein R⁹ is C₁ -C₈ alkylene and R¹⁰ is pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, or pyridyl and m is 1; and when R⁵ is C₁ -C₁₂ alkyl, which is substituted by C₂ -C₅ acyloxy or C₁ -C₄ alkoxy, R⁶ is unsubstituted C₁ -C₁₂ alkyl and m is 1, or a pharmaceutically acceptable salt thereof. 